The phospha-Michael addition reaction has emerged one of the most versatile and powerful synthetic tools for carbon-phosphorus bond formation because of its atom and step economic approach as well as many different products available with various substitution patterns, depending on both the acceptor and the donor nucleophiles (Trost (1991) Science 254: 1471-1477; Trost (1995) Angew. Chem. Int. Ed. 34: 259-281; Rulev (2014) RSC Adv. 4: 26002-26012; Enders et al. (2006) Eur. J. Org. Chem. 2006: 29-49). Highly functionalized and valuable phospha-Michael adducts are generated under the reaction conditions in one step (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903; Moonen et al. (2005) Angew. Chem. Int. Ed. 44: 7407-7411; Laghzizil et al. (2000) J. Fluorine Chem. 101: 69-73; Moiseev et al. (2007) Inorg. Chem. 46: 11467-11474; Luo et al. (2011) RSC Adv. 1: 698-705; Zhao et al. (2009) Chem. Eur. J. 15: 2738-2741; Simoni et al. (1998) Tetrahedron Lett. 39: 7615-7618; Li et al. (2014) Tetrahedron: Asymmetry 25: 989-996; Strappaveccia et al. (2016) Org. Biomol. Chem. 14: 3521-3525; Wen et al. (2010) Chem. Comm. 46: 4806-4808; Russo et al. (2010) Eur. J. Org. Chem. 2010: 6736-6739; Rai and Namboothiri (2008) Tetrahedron: Asymmetry 19: 2335-2338; Zhu et al. (2010) Angew. Chem. Int. Ed. 49: 153-156; Fu et al. (2007) Chem. Commun. 5058-5060; Wang et al. (2007) Adv. Synth. Catal. 349: 1052-1056; Lenker et al. (2012) J. Org. Chem. 77: 1378-1385; Li et al. (2014) Catal. Lett. 144: 1810-1818; Sobhani et al. (2013) Appl. Catal., A 454: 145-151; Sobhani et al. (2011) J. Organomet. Chem. 696: 813-817; Hosseini-Sarvari and Etemad (2008) Tetrahedron 64: 5519-5523).
Among the phospha-Michael adducts, γ-ketophosphonates and their phosphonic acid derivatives have received significant attention in recent years owing to their both biological properties and pharmaceutical applications. They exhibit a wide range of enzyme inhibitions such as matrix metalloprotease (MMP-2) inhibitor (Kluender et al. In U.S. Pat. Appl. U.S. 95-539409 951106, Chem. Abstr 1998, p. 161412) and osteoclastic acid phosphatase (OAP) inhibitor (Schwender et al. (1995) Bioorg. Med. Chem. Lett. 5: 1801-1806). In addition, they are versatile precursors for the synthesis of important γ-aminophosphonate compounds of anti-malarial drugs including Fosmidomycin and FR-900098 (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903; Jomaa et al. (1999) Science 285: 1573-1576; Andaloussi et al. (2011) J. Med. Chem. 54: 4964-4976). Furthermore, 3-phosphonopropionate has been identified as a promising dental adhesive (Ikemura et al. (2006) Dent. Mater. J. 25: 566-575).
Dialkyl phosphonate or trialkyl phosphites are the common Michael donors of this phospha-Michael addition in which only the trivalent phosphite form of the active nucleophile undergoes 1,4-addition to α,β-unsaturated carbonyls to form the γ-ketophosphonates (Zhao et al. (2009) Chem. Eur. J. 15: 2738-2741; Russo et al. (2010) Eur. J. Org. Chem. 2010: 6736-6739). With various methods available for the tautomerism in favor of the phosphite form between the phosphite and phosphonate equilibrium, dialkyl phosphonate Michael donors have been successfully applied for the synthesis of γ-ketophosphonates (Zhao et al. (2009) Chem. Eur. J. 15: 2738-2741; Simoni et al. (1998) Tetrahedron Lett. 39: 7615-7618; Li et al. (2014) Tetrahedron: Asymmetry 25: 989-996; Strappaveccia et al. (2016) Org. Biomol. Chem. 14: 3521-3525). On the other hand, application of the trialkyl phosphites to the phospha-Michael reaction is limited to a handful of examples and currently requires complex reaction conditions (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903; Moonen et al. (2005) Angew. Chem. Int. Ed. 44: 7407-7411). In 2007, Jørgensen and co-workers reported pyrrolidine-catalyzed enantioselective phospha-Michael addition of trialkyl phosphite (P(O-i-Pr)3) to the α,β-unsaturated aldehydes for β-phosphonylation, in combination of Brønsted acid (PhCO2H) and an external nucleophile (NaI) (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903). In addition, synthetic application of the precedent amine-catalyzed phospha-Michael reaction of the trialkyl phosphites to α,β-unsaturated aldehydes still faces two major synthetic hurdles: 1) The crucial step, the transformation of P(III) to P(V) (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903), must be performed via nucleophilic attack by additives. 2) Chemoselectivity is also another inherent difficulty in this type of addition due to the reversibility of the nucleophilic attack and competition between 1,2- and 1,4-addition (Maerten et al. (2007) J. Org. Chem. 72: 8893-8903; Moonen et al. (2005) Angew. Chem. Int. Ed. 44: 7407-7411; Moiseev et al. (2007) Inorg. Chem. 46: 11467-11474; Luo et al. (2011) RSC Adv. 1: 698-705; Strappaveccia et al. (2016) Org. Biomol. Chem. 14: 3521-3525).
Despite the plethora of known applications of phospha-Michael adducts, the preparation of these compounds has remained limited due to the use of additives and competing reaction products. Consequently, the development of a selective method of phosphonylation for accessing functionalized phosphonates is highly desirable in synthetic organic chemistry. These needs and others are met by the present invention.